Project 1) Selective effects of active metabolites of 1-Beta-D- arabinofuranosylcytosine (ara-C) in vivo. By using a well established tumor line, L1210, and an extensively studies antitumor agent, ara-C, the research work will be directed to gain insight into the following problems of chemotherapeutic relevance: Is DNA synthesis in L1210 leukemic cells and in host renewal systems differently affected by the active metabolite of ara-C (i.e., ara-CTP)? Are there differences between normal and leukemic cells in the relationship between dose of ara-C and duration of cytotoxic concentrations of ara-CTP? Are the lethal effects of inhibition of DNA synthesis by ara-CTP quantitatively similar in both kinds of cells? Are L1210 ascites cells and L1210 cells infiltrate in liver equally susceptible to the active metabolite? Project 2) Biochemical manipulation of ara-C metabolism and modulation of the relationship between DNA synthesis inhibition and cell killing in vivo. Nucleoside deaminase and alkaline phosphatase inhibitors will be used to manipulate ara-C metabolism in both normal and leukemic cells. Interference DNA synthesis with relation to lethal effect to cells will be analyzed in the absence and presence of deoxycytidine or of inhibitors of the synthesis of RNA or protein. Project 3) Kinase activity and the cytocidal effects of ara-C in resting and stimulated lymphoid organs. Previous studies on ara-C in this laboratory indicated that in inhibited DNA synthesis in thymus more potently and more persistently than in spleen or small intestine. Whether antigenically stimulated proliferating lymphoid cells in spleen are equally susceptible to ara-C as in thymus, and whether lymphocytes at different anatomic locations are metabolically different in regard to ara-CTP accumulation and susceptibility to inhibition of DNA synthesis will be analyzed.